Circulating blood cells are constantly replaced by newly developed cells. Replacement blood cells are formed in a process termed hematopoiesis which involves the production of at least eight mature blood cell types within two major lineages: (1) the myeloid lineage which includes red blood cells (erythrocytes), macrophages (monocytes), eosinophilic granulocytes, megakaryocytes (platelets), neutrophilic granulocytes, basophilic granulocytes (mast cells); and (2) the lymphoid lineage which includes T lymphocytes, and B lymphocytes (Burgess and Nicola, Growth Factors and Stem Cells (Academic Press, New York, 1983)). Much of the control of blood cell formation is mediated by a group of interacting glycoproteins termed colony stimulating factors (CSFs), including G-CSF, M-CSF, GM-CSF, and multi-CSF (also known as IL-3). These glycoproteins are so named because of the in vivo and in vitro assays used to detect their presence. Techniques for the clonal culture of hematopoietic cells in semisolid culture medium have been especially important in the development of in vitro assays. In such cultures, individual progenitor cells (i.e., cells developmentally committed to a particular lineage, but still capable of proliferation) are able to proliferate to form a colony of maturing progeny in a manner which is believed to be essentially identical to the comparable process in vive. The role of CSFs in hematopoiesis is the subject of many reviews, and is of great interest to clinical investigators who must treat blood diseases or deficiencies: e.g. Metcalf, The Hemopoietic Colony Stimulating Factors (Elsevier, N.Y., 1984); Clark and Kamen, Science, Vol. 236, pgs. 1229-1237 (1987); Sachs,Science, Vol. 238, pgs. 1374-1379 (1987); Dexter et al., eds., Colony Stimulating Factors (Dekker, N.Y., 1990); and Morstyn et al., Cancer Investigation, Vol. 7, pgs. 443-456 (1989).
The biological effects of the CSFs are mediated by specific cell surface receptors, which may consist of one or more components. Recently, several of these have been cloned and characterized, e.g. Gearing et al., EMBO J., Vol. 8, pgs. 3667-3676 (1989) (low affinity .alpha.-chain of human GM-CSF-receptor); Itoh et al., Science, Vol. 247, pgs. 324-327 (1990) (low affinity mouse IL-3-receptor); and Hayashida et al., Proc. Natl. Acad. Sci., Vol. 87, pgs. 9655-9659 (1990) (.beta.-chain of human GM-CSF-receptor). Besides contributing to an understanding of the signal transduction process, many of these receptors will be useful screening tools for agonists and antagonists of the natural ligand. In particular, such tools may lead to the development of non-protein agonists and antagonists which would obviate many of the difficulties associated with protein therapeutics, e.g. intravenous delivery, short serum half-life, and the like.